The present invention is generally in the field of genetic testing in dogs, and is specifically a genetic test for the mutation that causes Alport Syndrome (AS) or for a marker associated with the mutation.
Alport Syndrome (AS) is hereditary progressive glomerular nephritis which affects both humans and several breeds of the domestic dog. This disease is caused by mutations in the genes that encode certain proteins in the type IV collagen family. The type IV collagen family includes six distinct chains (a1-a6) which are major constituents of mammalian basement membranes throughout the body. AS specifically affects the glomerular basement membrane (GBM) of the kidney, causing a distinctive multilaminar splitting of the GBM ultrastructure, characteristic to the disease. These defects in the GBM contribute to the development of hematuria, proteinuria, and progressive renal injury which eventually lead to end stage renal disease (ESRD). Some human cases of AS have been reported to also be associated with hearing loss, ocular lesions and, in rare instances, leiomyomatosis.
AS is known to be transmitted genetically by three different mechanisms: X-linked (XL), autosomal recessive (AR), and autosomal dominant (AD). X-linked AS (XLAS) is caused by mutations in COL4a5 and is the most common form of AS, accounting for about 85% of human cases. Over 300 mutations in this gene causing human XLAS have been identified. In both the human and the dog, COL4a5 is located on the X chromosome. Autosomal recessive AS (ARAS) occurs less frequently, accounting for about 15% of human AS cases and is caused by loss of either COL4a3 or COL4A4. However, the causative mutations in these genes have not been identified. These genes are located on human chromosome 2 and canine chromosome 25. Mutations in COL4a3 or COL4a4 have also been reported to cause autosomal dominant AS (ADAS), which is the rarest form of AS, accounting for less than 5% of human cases.
Type IV collagen genes each encode a distinct a chain that can be assembled into three heterotrimers; a1/a1/a2, a3/a4/a5 and a5/a5/a6. The a1/a1/a2 and a3/a4/a5 heterotrimers are found in the GBM of the fetal and adult kidneys, respectively, while the a5/a5/a6 heterotrimer is found in the Bowman's capsule. Defects in any one of the three a chains in a heterotrimer impedes proper assembly and prevents deposition, of any of the proteins involved, into the GBM. The a3/a4/a5 heterotrimer is essential to the structure and function of the adult GBM, and, when absent, results in AS. Therefore, both XLAS and ARAS are characterized by the absence of COL4a3, COL4a4 and COL4a5 in the GBM of affected individuals.
While the underlying causes and modes of transmission of AS have been characterized, many aspects of the disease remain to be understood. As a result, the only treatment option is often renal transplant. Further investigation into this disease can be achieved through the use of available animal models. Therefore, it is clear that there is a need for a genetic test that permits the identification of animals with ARAS and carriers of ARAS.
It is therefore an object of the present invention to provide the mutation causative for ARAS in the dog.
It is a further object of the present invention to provide methods for detecting mutations in the COLa4 gene in dogs.